Geminal bisphosphonates, such as for example salts of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid (RISEDRONATE) or 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ALENDRONATE) have been used for already some time to treat bone diseases and for management of the metabolism of calcium.
Preparation of risedronic acid consists in the reaction of 3-pyridylacetic acid with phosphorous acid and phosphorus trichloride and subsequent hydrolysis of the resulting intermediates. A general method of this preparation of bisphosphonic acids was presented in JP 80-98193 (1980), JP 80-98105 (1980) of Nissan Chemical Industries and in the article of W. Ploger et al., Z. Anorg. Allg. Chem., 389, 119 (1972). Preparation of risedronate was presented in EP 186405 (1986) of Procter & Gamble.
Bisphosphonic acids are used in the form of various nontoxic and pharmaceutically acceptable esters, salts of alkali metals and alkaline-earth metals and their various hydrates. The form of the substance can have fundamental influence on its solubility and biological availability. The sodium and calcium salts are the preferred forms of risedronate.
3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid is used especially in the form of its monosodium salt (SODIUM RISEDRONATE). This salt, like a number of geminal bisphosphonic acids and their salts, can form hydrates. So far, anhydrous crystalline form of monosodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate, its monohydrate and pentahemihydrate have been described, namely in Procter & Gamble's application WO 01/56983 A2. Of the two mentioned hydrates, only the pentahemihydrate form is thermodynamically stable. The monohydrate spontaneously transforms to the stable pentahemihydrate.
The pentahemihydrate is prepared by forming a suspension of risedronic acid in water at about 60° C., adjusting the pH of the suspension to 4.5 to 5 with sodium hydroxide, adding isopropanol to the resulting solution at the same temperature, and gradually cooling the resulting suspension. The temperature of formation of first crystals is important for producing pure pentahemihydrate, which is most preferably maintained at between 50 to 70° C.
The monohydrate containing formulation, described in application WO 01/56983, therefore, necessarily absorbs water from the environment and changes its composition. This can be a significant source of instability of this form.
CZ patent 293349 (WO 2004/037252) describes higher hydrates of the monosodium, di-sodium and tri-sodium salts of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid. It has turned out that these salts do not take in any additional water from the air and it can be assumed that a composition comprising them will be more stable than that comprising the earlier-described mixture of the monosodium salt mono- and pentahemihydrates. The pentahydrate form of the monosodium salt is described therein, inter alia. The pentahydrate is one of alternative solutions to the earlier-described hemipentahydrate. It is stable especially in the wet environment. This hydrate was prepared from a solution of the monosodium salt in water, which is poured at 80° C. into isopropanol, cooled to −7 to −10° C.
Another solution is described in patent application WO 03/086355. The structure of the earlier-known hemipentahydrate was designated as polymorph A therein. The new crystalline form B, disclosed in this application, is the monohydrate; contrary to the earlier-known monohydrate, it is stable at normal conditions. In the invention, further crystalline forms C through H are also defined.
Methods of preparation of individual forms consist either in boiling a suspension of risedronic acid in a solution of sodium hydroxide in a mixture water-organic solvent, or in heating the monosodium salt to 100 to 200° C., or in exposing the salt to wet atmosphere for longer periods of time.
All forms of the monosodium salt of risedronic acid, described so far, have been crystalline. However, it turns out in many cases relating to pharmaceutically active substances that an amorphous form is biologically more available. Because biological availability of salts of bisphosphonic acids is generally very low—the organism usually makes use of about 1% of the total mass of the used active substance—it is desirable to find such forms that would have a larger utilizable portion.
The present invention, therefore, concerns new amorphous forms of the monosodium salt of risedronic acid (or risedronate sodium).